Nanoscale Mobility of the Apo State and TARP Stoichiometry Dictate the Gating Behavior of Alternatively Spliced AMPA Receptors
| Autor: | Mohammad Fahim Kadir, Camilo Navarrete, Christian Fuentes, R. Venskutonyte, M. Arsenault, Amanda M Perozzo, E.A. Santander, Y. Yan, John Michael Edwardson, Ryan P.D. Alexander, Derek Bowie, Jette S. Kastrup, Mark R. P. Aurousseau, Karla Frydenvang, Nelson P. Barrera, George B. Dawe |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Patch-Clamp Techniques Allosteric regulation Gating AMPA receptor Crystallography X-Ray Microscopy Atomic Force 03 medical and health sciences Mice Purkinje Cells 0302 clinical medicine Allosteric Regulation Protein Domains Cerebellum Animals Humans Protein Isoforms Receptors AMPA Receptor Protein Structure Quaternary Ion channel Chemistry General Neuroscience Cryoelectron Microscopy Glutamate receptor Membrane Proteins Protein Structure Tertiary Alternative Splicing 030104 developmental biology HEK293 Cells Biophysics Ionotropic glutamate receptor Ion Channel Gating 030217 neurology & neurosurgery Allosteric Site Ionotropic effect |
| Zdroj: | Neuron. 102(5) |
| ISSN: | 1097-4199 |
| Popis: | Summary Neurotransmitter-gated ion channels are allosteric proteins that switch on and off in response to agonist binding. Most studies have focused on the agonist-bound, activated channel while assigning a lesser role to the apo or resting state. Here, we show that nanoscale mobility of resting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (AMPA receptors) predetermines responsiveness to neurotransmitter, allosteric anions and TARP auxiliary subunits. Mobility at rest is regulated by alternative splicing of the flip/flop cassette of the ligand-binding domain, which controls motions in the distant AMPA receptor N-terminal domain (NTD). Flip variants promote moderate NTD movement, which establishes slower channel desensitization and robust regulation by anions and auxiliary subunits. In contrast, greater NTD mobility imparted by the flop cassette acts as a master switch to override allosteric regulation. In AMPA receptor heteromers, TARP stoichiometry further modifies these actions of the flip/flop cassette generating two functionally distinct classes of partially and fully TARPed receptors typical of cerebellar stellate and Purkinje cells. |
| Databáze: | OpenAIRE |
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